ABSTRACT In Uganda as in other sub-Saharan African countries, the Ministry of Health is in the process of adopting and implementing the new WHO 2010 PMTCT Guidelines. These Guidelines recommend using one of two ARV prophylaxis options for HIV-infected pregnant women who do not need antiretroviral therapy (ART) for their own health. Option A consists of maternal AZT prophylaxis throughout pregnancy and delivery, complemented by daily nevirapine for the infant from birth until one week after complete cessation of breastfeeding. Option B consists of triple ART for the mother from the 14th gestational week until one week after complete cessation of breastfeeding complemented by daily nevirapine for the infant for six weeks. Both options significantly reduce the risk of mother-to-child HIV transmission (MTCT) of HIV but their advantages and disadvantages in terms of operational feasibility, safety and acceptability as well as costs have not been evaluated. The WHO guidelines state that the choice for a preferred option should be made at a country level, after considering these advantages and disadvantages. The evidence needed to support such decision is presently lacking and critically needed for countries like Uganda that are trying to make informed choices about which option to roll out nationally. The overall goal of this operational research proposal is to compare the feasibility of delivering WHO PMTCT Options A and B in two urban Kampala hospitals and two rural hospitals in Uganda. We will enroll 600 eligible (CD4 >350) HIV- infected pregnant women into either option A or B for a total of 1,200 mother-infant pairs into the study. In each urban or rural area, one hospital will be assigned to option A and the other to Option B. In each hospital, 300 study participants will be enrolled and followed-up for 12 months post-partum. The primary aims of the study will be to compare options A and B implementation with regards to: Aim 1) maternal and infant PMTCT drug adherence measured by self report, pill counts and ARV drug detection in blood; Aim 2) maternal drug-associated severe adverse events and pregnancy outcomes; and infant safety; Aim 3) the cost-effectiveness of either option. The study will be powered to detect a difference of 10% or greater in drug adherence cumulatively and at four key time points in the cascade of PMTCT services, including the third trimester and three post-natal visits corresponding to the immunization and early infant HIV diagnosis schedules: 6 weeks post delivery, 6 months, and 12 months or at the time of breastfeeding cessation. Secondary endpoints will be to include vertical HIV transmission rates based on the presence of HIV DNA in infant blood at birth, 6 weeks of age, 6 months and 12 months of age; 12-month HIV-free survival and overall survival rates of HIV-exposed infants; and, incidence of subsequent pregnancies in the 12-month post-partum follow-up period. We will use focus group discussions and key informant interviews to assess the acceptability of either PMTCT option among HIV-infected mothers, service providers and community health leaders. The results of this study will provide critical evidence to inform operational decisions regarding the feasibility of the current WHO PMTCT recommendations in the context of resource-limited settings.